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dc.contributor.authorHoe, See LE
dc.contributor.authorFoster, SR
dc.contributor.authorWendt, L
dc.contributor.authorPatel, HH
dc.contributor.authorHeadrick, JP
dc.contributor.authorPeart, JN
dc.date.accessioned2019-06-07T01:34:29Z
dc.date.available2019-06-07T01:34:29Z
dc.date.issued2019
dc.identifier.issn0022-3565
dc.identifier.doi10.1124/jpet.118.251660
dc.identifier.urihttp://hdl.handle.net/10072/384322
dc.description.abstractSustained ligand-activated preconditioning (SLP), induced with chronic opioid receptor (OR) agonism, enhances tolerance to ischemia/reperfusion injury in young and aged hearts. Underlying mechanisms remain ill-defined, although early data implicate phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) during the induction phase, and β2-adrenoceptor (β2-AR), Gs alpha subunit (Gαs), and protein kinase A (PKA) involvement in subsequent cardioprotection. Here, we tested for induction of a protective β2-AR/Gαs/PKA signaling axis with SLP to ascertain whether signaling changes were PI3K-dependent (by sustained cotreatment with wortmannin), and whether the downstream PKA target Rho kinase (ROCK) participates in subsequent cardioprotection (by acute treatment with fasudil). A protected phenotype was evident after 5 days of OR agonism (using morphine) in association with increased membrane versus reduced cytosolic levels of total and phosphorylated β2-ARs; increased membrane and cytosolic expression of 52 and 46 kDa Gαs isoforms, respectively; and increased phosphorylation of PKA and Akt. Nonetheless, functional sensitivities of β2-ARs and adenylyl cyclase were unchanged based on concentration-response analyses for formoterol, fenoterol, and 6-[3-(dimethylamino)propionyl]-forskolin. Protection with SLP was not modified by ROCK inhibition, and changes in β2-AR, Gαs, and PKA expression appeared insensitive to PI3K inhibition, although 5 days of wortmannin alone exerted unexpected effects on signaling (also increasing membrane β2-AR and PKA expression/phosphorylation and Gαs levels). In summary, sustained OR agonism upregulates cardiac membrane β2-AR expression and phosphorylation in association with increased Gαs subtype levels and PKA phosphorylation. While Akt phosphorylation was evident, PI3K activity appears nonessential to OR upregulation of the β2-AR signal axis. This opioidergic remodeling of β2-AR signaling may explain β2-AR, Gαs, and PKA dependence of SLP protection.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
dc.relation.ispartofpagefrom37
dc.relation.ispartofpageto46
dc.relation.ispartofissue1
dc.relation.ispartofjournalJOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
dc.relation.ispartofvolume369
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3214
dc.titleRegulation of the beta-Adrenergic Receptor Signaling Pathway in Sustained Ligand-Activated Preconditioning
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorPeart, Jason N.
gro.griffith.authorWendt, Lauren
gro.griffith.authorHeadrick, John P.


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